Samarium Barbier reaction

The elucidation of the mechanism of the samarium Barbier reaction has proved particularly taxing (Scheme 10.26) and represents a classic example of how to investigate radical mechanisms [21, 22]. To complicate the investigation of the mechanism, both alkyl halides and ketones can be reduced by Sml2 (see above). Four feasible mechanisms can be postulated as shown in Scheme 10.26. Mechanisms 1 and 2 have reduction of the alkyl halide first to yield the alkyl radical, and mechanisms 3 and 4 have reduction of the ketone to the ketyl first. 

Scheme 10.28 Use of the 5-hexenyl radical clock to determine Arrec n for primary alkyl radicals by Smb in a samarium Barbier reaction (Ar = p-methoxyphenyl).

Sml2 (and Cp2Sm also) finds use as a coupling agent34 as in the so-called samarium Barbier reaction ... 

The transformation is only moderately stereoselective in this situation and the stereochemical outcome of the reaction is explained by a complexation of the samarium atom by the acetamido group in the kinetic a-Sm(IIl) species 186, slowing down the isomerization to the /3-species. The anomeric selectivity is completely lost when operating with the acetylated sulfone 187. A solution to restore a selective reaction and to access to C-glycosides mimicking the biologically ubiquitous /3-GlcNAc motif, relies on this intermolecular samarium-Barbier reaction followed by an oxidation-isomerization sequence [91] (O Scheme 39). 

Curran, D. P., Gu, X., Zhang, W., Dowd, P. On the mechanism of the intramolecular samarium Barbier reaction. Probes for formation of radical and organosamarium intermediates. Tetrahedron 1997, 53, 9023-9042. 

An interesting application of the samarium Barbier reaction was applied using 4-(a-iodomethyl)- or 2-(a-iodomethyl)oxazoles 136 with aliphatic aldehydes. This reaction is compatible with the presence of esters and common ether protecting groups <050L4099>. The scope of the reaction is somewhat limited by the low yields obtained with a-alkoxy aldehydes. 

In 1980 we noticed that a samarium Barbier reaction between n-butyl iodide and 2-octanone which needed 8 h at 65 °C could be run in 3 h at room temperature in the presence of a catalytic amount (2 mol%) of ferric chloride [15]. This experiment was inspired by the known catalytic effect of the Fe3+ ion on the Ln2+/Ln3+ conversion [146]. The beneficial influence of the Fe(III) derivative in reactions mediated by Sml2 has been used by several authors in various processes. Thus, Molander et al. described a general procedure for five- and six-mem-bered ring annulation starting from 2-(oo-iodoalkyl) cycloalkanones [ 147]. 

The mechanism for the transformation of 5 to 4 was not addressed. However, it seems plausible that samarium diiodide accomplishes a reduction of the carbon-chlorine bond to give a transient, resonance-stabilized carbon radical which then adds to a Smni-activated ketone carbonyl or combines with a ketyl radical. Although some intramolecular samarium(n)-promoted Barbier reactions do appear to proceed through the intermediacy of an organo-samarium intermediate (i.e. a Smm carbanion),10 ibis probable that a -elimination pathway would lead to a rapid destruction of intermediate 5 if such a species were formed in this reaction. Nevertheless, the facile transformation of intermediate 5 to 4, attended by the formation of the strained four-membered ring of paeoniflorigenin, constitutes a very elegant example of an intramolecular samarium-mediated Barbier reaction. 

Barbier reaction Samarium(II) iodide, 270 Benzoannelation Chromium carbene complexes, 82 Dicarbonylcyclopentadienylcobalt, 96 Ethyl (Z)-3-bromoacryIate, 130 Grignard reagents, 138 Methyl acrylate, 183 Methyllithium, 188 Ruthenium(III) chloride, 268 Benzoin condensation Benzyltriethylammonium chloride, 239 3-EthyIbenzothiazolium bromide, 130 Benzoylation (see also Acylation) Cadmium, 60 Dibutyltin oxide, 95 Birch reduction Birch reduction, 32... 

Reductive coupling of dialdehydes may also be accomplished by use of samarium(II) iodide514. The reactions is stereoselective and has been used to prepare myo-inositol derivatives (equation 132)515. The equivalent reaction, using low-valent titanium species as catalysts, results in a mixture of products516. The production of cyclic /1-amino alcohols may be accomplished in good yields, and with a high degree of cis selectivity by the treatment of carbonyl hydrazones with samarium(II) iodide (equation 133)517. This reaction is effectively equivalent to an aza-Barbier reaction. 

Sml2, which can be prepared conveniently from samarium powder and 1,2-diiodoethane in THF, finds application as a versatile one-electron reducing agent in organic synthesis. Two typical synthetic procedures mediated by Sml2 are the pinacol coupling of aldehydes and the Barbier reaction, as shown in the following schemes ... 

In contrast, the Barbier reactions of 2-acetamido-2-deoxy sugars with ketones showed a preference for the formation of 1,2-m-C-glycoside products (Scheme 7.39). This was attributed to the complexation of the C2-acetamido group to the glycosyl samarium, thereby reducing the configurational lability of the organometallic species.78,80,81... 

The mechanism of the intramolecular samarium-initiated Barbier reaction is still a matter of debate [80-82], One of several mechanistic possibilities is primary reductive generation of the ketyl radical anion which can subsequently initiate a second... 

The samarium(ll)-mediated Barbier reaction has been used as an alternative to the deprotonation chemistry to generate 2-alkyl-metallated oxazoles (Scheme 43). This reaction is very useful for the coupling of 2-iodomethyl oxazoles and aliphatic aldehydes. However, reactions with aromatic aldehydes gave mainly pinacol coupling products <20050L4099>. 

In the last 10 years, the Barbier reaction method has been utilized more with other metals than with magnesium. The number of papers published on the lithium-Barbier reaction is three to four times that of magnesium [149-157]. Reactions can be carried out at lower temperatures than possible with Mg-Barbier reactions and yields are often very high with fewer by-products. Other metals of note are samarium, in the form of its diiodide [158-165], and zine [166-169], the metal of choice for the pre-Barbier one-step reaction, and the classic Reformatsky reaction. In situ reactions have been reported for A1 [170], Ce [171], Cd [172,173], Ga [174], Hg [175], In [176], Mn [177], Pb [178-180], Sb [181-183], Sn [184,185], and Ti [186]. An excellent paper by Li reviews the Barbier reactions of many metals in aqueous media [187]. 

Exceptionally clean cyclization can be accomplished by utilizing conjugated enones as precursors for the Barbier reaction (equation 43). High diastereoselectivity is achieved in these reactions, and under the mild conditions required for cyclization the TMS ether protecting group remains intact. It is also interesting that a neopentyl halide is effective in the cyclization. This result would appear to exclude an 5N2-type displacement of an organic halide by a samarium ketyl as a possible mechanism for the Smh-promoted intramolecular Barbier reaction. 

Samarium diiodide is a one electron reductant that is capable of reducing both alkyl halides and carbonyl compounds. The rate of the reduction depends on the nature of the substrate and the reaction conditions. The mechanism of the addition of alkyl halides to carbonyls was extensively studied. In case of the samarium Grignard processes, it was concluded that the reaction proceeds through an organosamarium intermediate. However, the mechanism of the samarium Barbier processes is not fully understood and there is no unambiguous evidence in favor of any of the possible pathways. 

Curran, D. P., Fevig, T. L., Totleben, M. J. Sequential radical cyclization-organometallic addition. The mechanism of the samarium(ll) mediated Barbier reaction in the presence of hexamethylphosphoric triamide. Syn/ett 1990, 773-774. 

Related reactions Barbier reaction, Grignard reaction, Kagan-Molander samarium diiodide coupling ... 

Samarium iodide has been used to bring about reductive photo-dehalogenation of 1,1-dichlorocyclopropane. The results and the efficiency of the reaction are shown in Scheme 5. The process, a Barbier reaction, is brought about using visible light. The yields of product are enhanced by the addition PhSH as a hydrogen donor. 

Vinylogous Barbier reaction,4 Smlj (2 equiv.) can effect cyclization of the unsaturated iodo ketone 1 in THF containing DMPU (or HMPA) to give a bicyclic samarium enolatc (a) that can be trapped by an aldol reaction. 

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